Association of genetic variations in the NOS1 gene with insomnia, sleep duration and obstructive sleep apnea-related clinical quantitative traits

Objective·To explore the correlation between the genetic variations rs7305526 and rs11615756 of nitric oxide synthase 1 (NOS1) and the human sleep traits, including insomnia, sleep duration, and clinical quantitative traits related to obstructive sleep apnea (OSA).Methods·The NOS1 gene expression pattern at the whole-brain level using the Allen Human Brain Atlas dataset was analyzed. Subsequently, we performed expression quantitative trait locus (eQTL) analysis to investigate the impact of rs7305526 and rs11615756 on NOS1 gene expression. Regression analysis was conducted to assess the associations between rs7305526 and rs11615756 with insomnia and sleep duration based on the United Kingdom Biobank (UKB) Genome-Wide Association Study (GWAS) dataset. Furthermore, we explored the relationships between rs7305526 and rs11615756 with clinical quantitative traits of OSA, such as respiratory events, oxygen levels, and sleep traits, using clinical monitoring data from the Shanghai Sleep Health Study Cohort (SSHS) based on standard polysomnography (PSG).Results·The NOS1 gene demonstrated elevated levels of expression in various brain regions crucial for regulating sleep, namely the amygdala, basal forebrain, striatum, and thalamus, as well as in the respiratory center, including the mesencephalon and pontine tegmentum. In contrast, the expression level of NOS1 gene was significantly reduced or absent in areas such as the cerebral cortex and cerebellum. Variants rs7305526 and rs11615756 were significantly negatively correlated with the expression levels of NOS1 in the cerebral cortex. Additionally, rs11615756 was also significantly negatively correlated with the expression level of NOS1 in the amygdala. Analysis of the UKB GWAS data revealed that the variant rs7305526 was not significantly associated with either insomnia or sleep duration, while rs11615756 demonstrated a noteworthy negative correlation specifically with sleep duration. Data obtained from the SSHS indicated a significant association between rs7305526 and alterations in clinical quantitative traits of OSA, including lowest pulse blood oxygen saturation (LSpO2), apnea-hypopnea index (AHI), and the ratio of non-rapid eye movement (NREM) stage 2 sleep duration. Although rs11615756 showed a notable negative correlation solely with the quantity of NREM stages 2 and 3, both rs11615756 and rs7305526 showed significant correlations with some respiratory events and oxygen traits after stratification according to the severity of OSA.Conclusion·Genetic variants of NOS1 gene are respectively associated with human sleep duration traits and OSA-related variables, suggesting that NOS1 gene plays a crucial regulatory role in human sleep and clinical quantitative traits of OSA. The regulation of sleep traits by rs7305526 (C>A) is independent of its regulation of respiratory events and oxygen traits.